Selenium is an essential trace element in the diets of mammals because of its presence in selenocysteine- containing proteins. Clinical trials and animal studies have demonstrated the potent cancer prevention activity of selenium;however, mechanisms by which it decreases cancer incidence are not understood. This deficiency precludes identification of subsets of the human population that benefit from dietary selenium supplementation, as well as those who do not. At optimal concentrations of selenium in the diet, selenoproteins account for the major pool of this trace element in mammalian organs and tissues. Functionally characterized selenoproteins exhibit redox activities, and imbalance in the levels of these proteins affects redox homeostasis. The PI recently identified a full set of selenoproteins in mammals, many of which are redox proteins. Among them, the 15 kDa selenoprotein (Sep15) emerged as the major candidate for mediating the cancer prevention effect of dietary Se. In the previous funding cycle, the PI's research team carried out initial functional and structural characterization of Sep15, its homologs and interacting partners, and developed Sep15 mouse models. The role of selenoproteins and selenocompounds in the development of hepatic tumors in mice was also addressed. The research team is now poised to benefit from this foundation and proposes to characterize in detail the functions of Sep15 and members of its protein family and to use novel mouse models of hepatic selenoprotein deficiency to directly determine the role of selenoproteins in cancer prevention. This work will be guided by three questions (specific aims): 1) What is the role of Sep15 in oxidative protein folding? 2) What is the biological function of Sep15? and 3) What roles do selenoproteins play in cancer prevention? These questions will be addressed using a combination of biochemical and cell biology studies and animal models. Relevance to the public health: The trace element selenium protects against prostate, colon, lung, and liver cancer, but the mechanism of this effect and forms of selenium that contribute most to this protection are unknown. This research will examine selenoproteins implicated in cancer prevention and the factors affecting their functions. This research may have direct implications for human studies and may lead to the ability to identify segments of the human population at risk of developing cancers that can be prevented by selenium.